Cell death is a fundamental aspect of animal development. Many cells die during the normal development of both vertebrates (Glucksmann, Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951)) and invertebrates (Truman, Ann. Rev. Neurosci. 7:171-188 (1984)). These deaths appear to function in morphogenesis, metamorphosis and tissue homeostasis, as well as in the generation of neuronal specificity and sexual dimorphism (reviewed by Ellis et al., Ann. Rev. Cell Biol. 7:663-698 (1991)). An understanding of the mechanisms that cause cells to die and that specify which cells are to live and which cells are to die is essential for an understanding of animal development.
The nematode Caenorhabditis elegans is an appropriate organism for analyzing naturally-occurring or programmed cell death (Horvitz et al., Neurosci. Comment. 1:56-65 (1982)). The generation of the 959 somatic cells of the adult C. elegans hermaphrodite is accompanied by the generation and subsequent deaths of an additional 131 cells (Sulston and Horvitz, Dev. Biol. 82:110-156 (1977); Sulston et al., Dev. Biol. 100:64-119 (1982)). The morphology of cells undergoing programmed cell death in C. elegans has been described at both the light and electron microscopic levels (Sulston and Horvitz, Dev. Biol. 82:100-156 (1977); Robertson and Thomson, J. Embryol. Exp. Morph. 67:89-10 100 (1982)).
Many genes that affect C. elegans programmed cell death have been identified (reviewed by Ellis et al., Ann. Rev. Cell Biol. 7:663-698 (1991)). The activities of two of these genes, ced-3 and ced-4, are required for the onset of almost all C. elegans programmed cell deaths (Ellis and Horvitz, Cell 44:817-829 (1986)). When the activity of either ced-3 or ced-4 is eliminated, cells that would normally die instead survive and can differentiate into recognizable cell types and even function (Ellis and Horvitz, Cell 44:817-829 (1986); Avery and Horvitz, Cell 51:1071-1078 (1987); White et al., Phil. Trans. R. Soc. Lond. B. 331:263-271 (1991)). Genetic mosaic analyses have indicated that the ced-3 and ced-4 genes most likely act in a cell autonomous manner within dying cells, suggesting that the products of these genes are expressed within dying cells and either are cytotoxic molecules or control the activities of cytotoxic molecules (Yuan and Horvitz, Dev. Biol. 138:33-41 (1990)).